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An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb.

Published byYanti Iskandar Modified over 6 years ago

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Presentation on theme: "An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb."— Presentation transcript:

1 An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb ischemia  Donghua Xie, MD, PhD, Yongjun Li, MD, PhD, Erika A. Reed, Shelley I. Odronic, Christopher D. Kontos, MD, Brian H. Annex, MD  Journal of Vascular Surgery  Volume 44, Issue 1, Pages (July 2006) DOI: /j.jvs Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

2 Fig 1 A, Vascular endothelial growth factor (VEGF) messenger RNA copy number (ischemic limb minus nonischemic limb for each animal) and protein expression is shown from group 1 mice, which were injected 7 days after the induction of hindlimb ischemia. Tibialis anterior (TA) and gastrocnemius (GAS) muscle was harvested 3 days after injection. The plasmid studies were performed on the active agent zinc-finger DNA-binding transcription factor 32E plasmid (ZFP-32E PL), a plasmid with the same backbone but no insert (P-Vax PL), and a nuclear localizing β-galactosidase (β-gal PL), but statistical comparisons were done using the ZFP-32E PL vs β-gal PL. ELISA, Enzyme-linked immunoabsorbent assay. B, Bar graphs show mean ± standard deviation of value to show the differences ZFP-32E PL vs β-Gal PL and ZFP-32E adenovirus (AV) vs β-gal AV. TRT-PCR, TaqMan real-time reverse transcriptase polymerase chain reaction. *P < .05 vs β-gal. **P < .01 vs β-gal. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

3 Fig 2 A, Representative alkaline phosphatase stains show that capillary density in the ischemic skeletal muscle treated with the zinc-finger DNA-binding transcription factor 32E (ZFP-32E) adenovirus (AV) is higher than (B) in muscle treated with β-galactosidase (β-gal) AV at 7 days after injection. Dark blue dots indicate capillaries (×100 original magnification, CD-31 staining). C, The table shows the quantitative data of the two complimentary measures of vascular density. Note that the alkaline phosphatase data were analyzed as both capillaries/mm2 as well as capillaries per fiber. The CD-31 data were analyzed as percent positive nuclei. Symptoms show the P values for the t tests of the individual ZFP regimen to the matched β-gal regimen. TA, Tibialis anterior; GAS, gastrocnemius. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

4 Fig 3 Graphic representation of the quantitative assessments of vascular density performed by the alkaline phosphatase and CD31 staining, in the ischemic and nonischemic limbs from the different treatment groups, respectively. Panels A and C are of the tibialis anterior (TA) muscle and, B and D are of the gastrocnemius (GAS) muscle. In all panels, values in the nonischemic limb were similar. Because values amongst the β-galactosidase groups were very similar, they were combined for this graph. Statistical comparisons were done in a manner identical to those in Fig 2 (ie, a single dose of plasmid vs a single dose of plasmid). ZFP-32E, Zinc-finger DNA-binding transcription factor 32E; AV, adenovirus; PL, plasmid. *P < .05. **P < .01. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

5 Fig 4 A, Representative examples of terminal deoxynucleotidyl transferase (TdT) biotin-dUTP nick-end labeling (TUNEL) staining from zinc-finger DNA-binding transcription factor 32E (ZFP-32E) adenovirus (AV) treatment (top) and a β-galactosidase (β-gal) AV treatment (bottom) at 7 days after injection. TUNEL- positive nuclei (brown color, arrows) are visible in the ischemic muscle from both groups, but the number of apoptotic cells in the ZFP-32E treated arm is much lower than in the β-gal treatment (×200 original magnification). B, Quantitative assessments of the extent of apoptosis are expressed both as the fraction of positive nuclei and the number of TUNEL + nuclei per unit area. The level of significance for the paired t test of the treatment vs no-treatment are shown and labeled below. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

6 Fig 5 Graphic representation of the quantitative assessments of proliferation and apoptosis in the ischemic and nonischemic limbs from the different treatment groups. A and C, Tibialis anterior (TA) muscle. B and D, Gastrocnemius (GAS) muscle. In all panels, values in the nonischemic limb were quite similar. Because values amongst the β-galactosidase groups were very similar and in some cases identical, they were combined for this graph. Statistical comparisons were done in a manner identical to those in Fig 2 (ie, a single dose plasmid against a single dose plasmid). ZFP-32E, Zinc-finger DNA-binding transcription factor 32E; AV, adenovirus; PL, plasmid. **P < .01 respectively. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

7 Fig 6 The three panels show the changes in the perfusion ratios over time for each zinc-finger DNA-binding transcription factor (ZFP) treatment vs β galactosidase (β-gal) control. Time point 1 represents the value before injection of the agent or β-gal control, time point 2 is 7 days after injection, time point 3 is 14 days after, time point 4 is 21 days after, and time point 5 is 28 days after injection. Data were analyzed using a standard ANOVA repeated measures analysis. In the top panel, 1 dose of the ZFP-32E plasmid (PL) was superior to 1 dose of the β-gal PL by 7.7% (P = .004) and 1 dose of the ZFP-32E PL became significantly greater over time compared to 1 dose of the β-gal plasmid (P = .009). In the middle panel, 2 doses of the ZFP-32E PL was superior to 2 doses of the β-gal PL by 11.2% (P < .001), and 2 doses of the ZFP-32E PL became significantly greater over time compared with 2 doses of the β-gal PL (P < .001). In the bottom panel, 1 dose of the ZFP-32E adenovirus (AV) was superior to 1 dose of the β-gal AV by 12.3% (P < .001), and 1 dose of the ZFP-32E AV became significantly greater over time compared with 1 dose of the β-gal AV (P < .001). VEGF, Vascular endothelial growth factor. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

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